In this article the authors comment the recently published LION-HEART study about intermittent administration of levosimendan in advanced heart failure. Both primary and secondary endpoints were positive in this trial. The authours point out that both in the LION-HEART and LevoRep studies safety and tolerability were favourable for levosimendan. In the text it is highlighted that the current study LEODOR, a prospective trial with firm clinical endpoints, is meant to confirm the encouraging results.

The present, open study included 60 patients. The levosimendan group received 0.1 mcg/kg/min of the drug beginning at the night before surgery (without a loading dose) and continued for 24 h including the intraoperative period. Levosimendan significantly increased cardiac index, decreased PCWP and serum lactate, as well as reduced the incidence of atrial fibrillation, low cardiac output syndrome and acute kidney injury compared to the control group. Pre- and intraoperative infusion of levosimendan, without a loading dose, aids in successful conduct of off-pump surgery in this clinical setting.

In the present meta-analysis, all three recent large clinical trials were included (CHEETAH, LEVO-CTS, LICORN). The total number of patients was 3,247 from 25 studies, the meta-analysis thus being the largest in cardiac surgery. In the mortality analysis, only 19 studies were included. The results show that levosimendan reduced 30-day mortality significantly compared to the control group (OR 0.63; 95% CI 0.47-0.84), but this reduction remained evident only in the subgroup of patients with a low ejection fraction of < 50% (OR 0.49; 95% CI 0.35-0.70). Levosimendan also significantly reduced the incidence of acute kidney injury, renal replacement therapy use, and duration of ICU stay. These results are in close agreement with the meta-analysis of Tena et al (2018), which is commented in this issue of Simdax BKU.

The present meta-analysis assessed some relevant hemodynamic and neurohumoral variables. The patient material included 257 patients from 7 studies, of which about half of the patients received levosimendan and the other half served as controls (dobutamine, furosemide, or no comparator). The number of patients analysed for each variable does not seem to match the reported total number of patients. Levosimendan significantly reduced BNP levels and increased left ventricular ejection fraction. The results, at least in the way they are presented in this paper, seem a little confusing. Further studies on the subject are warranted.

The authors conclude that despite multiple treatment modalities, no consistent mortality benefit has been observed in AHF. The paragraph about levosimendan is short, and only the LIDO, REVIVE and SURVIVE studies are mentioned. However, the authors recommend considering the use of levosimendan in hypotensive heart failure. However, a bolus dose should be given only in patients with a systolic blood pressure above 100 mmHg.

By this open uncontrolled trial the authors found that a single 24-hour infusion of levosimendan improved haemodynamics also in stable chronic heart failure. Cardiac output (measured with a non-invasive rebreathing method) increased, and peripheral resistance decreased. The small sample size of 23 patients and the absence of a control group limit the interpretation of the results.

The effect of inotropic or vasodilator drugs on mortality was analysed in totally 2001 patients with cardiogenic shock or low cardiac output syndrome from 13 studies. Many of the studies had serious limitations. The review presents low-quality evidence that levosimendan reduces short-term mortality significantly compared to dobutamine. However, this survival benefit is not confirmed in long-term follow-up. At present there are no robust data to support any distinct inotropic or vasodilator drug to reduce mortality in this clinical setting.

A total of 816 patients from 10 trials with very different study designs were included in this meta-analysis. There was no significant difference in mortality between the levosimendan group and the group receiving standard inotropic therapy. The trial sequential analysis indicated that the evidence was inconclusive. Further randomised, controlled clinical trials are needed to assess the effect of levosimendan in septic shock.

Levosimendan is safe and well tolerated in patients undergoing cardiac surgery with cardiopulmonary bypass who have low LVEF and are at risk of the development of postoperative low cardiac output syndrome. The lack of any deterioration in survival is particularly noteworthy. Levosimendan safety and efficacy confirmed also after the latest three clinical trials.